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Methods for the synthesis of pyridoxamine

a technology of pyridoxine and pyridoxamine, which is applied in the direction of biocide, drug composition, metabolic disorder, etc., can solve the problems of non-selective oxidation of the second hydroxymethyl group at the 5 and the problem of pyridoxine oxidation is problemati

Active Publication Date: 2007-05-08
PRAETEGO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The invention provides methods for synthesizing the compound pyridoxamine (I) and its salts, as well as intermediate compounds. The methods involve protecting hydroxyls, converting a compound to a cyclic imide substituent, and converting the compound to a compound of formula (I). The invention also relates to compositions comprising pyridoxamine (I) and other compounds, as well as methods of treating or preventing various conditions or disease states by administering pyridoxamine (I) or its salts. The invention also includes a zwitterion structure."

Problems solved by technology

However, the oxidation of pyridoxine is problematic at the scale required for commercial manufacturing for several reasons, including the need to rapidly remove large amounts of solid oxidants to minimize the potential for continuing oxidation reactions.
Such overoxidation not only can convert pyridoxal to pyridoxic acid but can also lead to non-selective oxidation of the second hydroxymethyl group at the 5-position.
Other difficulties can be encountered subsequent to the formation of pyridoxal.
Hydroxylamine is a dangerous reagent to handle on an industrial scale due to its instability, its high reactivity and its toxicity.
This is also an unfavorable reagent for large scale manufacturing.
Reduction with hydrogen catalysts such as platinum or palladium is possible, but this route is expensive, difficult to control, and difficult to scale up.
Over-reduction can lead to the generation of deoxy impurities that may be toxic anti-metabolites contaminating the API.
However, non-oxidative methods appear to have been rarely reported in the literature.
Thus even if the yield can be made acceptable, this will remain a hindrance at the large (manufacturing) scale needed to produce API.
There are currently no or few processes described that are suitable for the large scale economical manufacturing required to produce pyridoxamine or salts thereof, for use as an API that is free of impurities at levels acceptable for FDA-approved drugs.

Method used

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  • Methods for the synthesis of pyridoxamine
  • Methods for the synthesis of pyridoxamine
  • Methods for the synthesis of pyridoxamine

Examples

Experimental program
Comparison scheme
Effect test

example 1

Acetylation of Pyridoxine (II)

[0166]

Synthesis

[0167]A 160 L reactor was inertised and charged with pyridoxine hydrochloride (II) (15.915 kg) in TBME (46 L). Acetic anhydride (3.25 eq., 24.5 L) was added and the suspension was heated to 50° C. Triethylamine (4 eq., 43 L) was added slowly over a period of 1 hour. During the addition of triethylamine, the inner temperature increased to 65° C. The mixture was stirred at reflux temperature for 1.5 hours. The reaction was completed when TLC analysis showed complete acetylation of pyridoxine.

Workup

[0168]The reaction was cooled to 10° C., filtered, and the precipitate was washed with TBME (3×18 L). The combined organic layers were stirred for 25 minutes with saturated NaHCO3 (sat. 40 L soln., pH 6–7). The organic and aqueous layers were separated, with the aqueous layer extracted again with TBME (20 L). The combined organic layers were extracted with saturated NaHCO3 (40 L, pH 9). Analysis by 1H NMR showed no residual acetic anhydride. The o...

example 2

Preparation of Phthalimido-Derivative (D)

[0173]

[0174]A 160 L reactor was inertised and charged with the product from Example 1 in TBME (22.367 kg (C), 121 L). The solution was concentrated to a volume of about 40 L, under reduced pressure and a jacket temperature of 60° C. To the reduced volume was added DMSO (50 L). The distillation of TBME was continued until 1H NMR showed 5.4 mol % of residual TBME (compared to amount of (C); limit: 10 mol %). To this was added DMSO (7.5 L), phthalimide potassium salt (1.3 eq., 18.211 kg), and THF (9 L) and the mixture was stirred at 40° C. for 34.hr. At this point 1H NMR showed 98.2% conversion to (D).

[0175]The reaction mixture was cooled to 20° C. and divided into two portions (2×50 L). To each portion THF (45 L and 44.5 L), water (11 L and 12 L), and half-saturated NaCl (25 L and 23.5 L) were added, and the resulting aqueous and organic layers were separated. The combined aqueous layers were extracted with THF (3×20 L). The combined organic la...

example 3

Preparation of Methylamide Derivative of Pyridoxamine (V)

[0181]

[0182]A 160 L reactor was inertised and charged with the product of Example 2 in THF (26.216 kg (D) in 133 L). The solution was heated to 48–50° C. and propylamine (4 eq., 25.1 L) was added over a period of 33 minutes (temperature increased to 55° C. during addition). The reaction mixture (solution) was stirred at 65° C. for 15 h. A suspension formed. 1H NMR showed conversion >99% (compared to intermediate with signal at δ=5.23 ppm, 2H).

[0183]The suspension was cooled to 5° C. over a period of 1 h and stirred at this temperature for 40 min. The suspension was filtered over a wet celite bed (2.403 kg Celite, 10 L THF) to give a clear orange mother liquid. The filtration was quite slow (˜7.5 h). The filter cake (crude 1#1—phthalic acid dipropylamide) was washed with cold (5° C.) THF (2×48 L). The combined organic layers (215 L) were concentrated to a volume of about 30 L at a 60° C. jacket temperature under reduced pressur...

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Abstract

The invention provides non-oxidative methods for the large scale manufacture of pyridoxamine (I) (4-aminomethyl-3-hydroxy-5-hydroxymethyl-2-methylpyridine):and salts thereof.The invention also provides intermediate compounds for the synthesis of pyridoxamine, as well as compositions and methods for the treatment and / or prevention of conditions associated with the formation of post-Amadori advanced glycation end-products.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application (application Ser. No. 11 / 054,527) claims priority from U.S. Provisional Application Ser. No. 60 / 543,115, filed Feb. 9, 2004, which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]The invention relates to methods for the synthesis of pyridoxamine, pyridoxamine derivatives, or pharmaceutically acceptable salts thereof. More specifically, the invention relates to synthetic methods for the non-oxidative preparation of pyridoxamine and salts thereof, and its use in methods of treating mammals. The invention also relates to compounds and compositions comprising pyridoxamine produced by such methods.BACKGROUND OF THE INVENTION[0003]Pyridoxamine (chemical name 4-aminomethyl-3-hydroxy-5-hydroxymethyl-2-methylpyridine; alternate names 4-(aminomethyl)-5-(hydroxymethyl)-2-methylpyridin-3-ol, and 4-(aminomethyl)-5-hydroxy-6-methyl-3-pyridinemethanol) is a promising pharmaceutical agent for the preventio...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D213/62A61K31/4415C07D213/66C07D213/67C07D401/12
CPCC07D213/66C07D213/67C07D401/06C07D401/12A61P13/12A61P25/00A61P27/02A61P3/06A61P9/10A61P3/10
Inventor KHALIFAH, RAJAKEILITZ, ROLANDKOELLNER, CHRISTOPHDEGENHARDT, THORSTENBRAND, STEPHEN ROBERT
Owner PRAETEGO INC
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